Cardiotonic agents have been used for the treatment of heart failure for some time with digitalis continuing to be one of the principle pharmacologic agents used for this purpose, although the cardiac glycosides as a class do have some limitations. Cardiac output is regulated by the integration of the contractile state of the heart and the dynamics of the peripheral circulatory system. When the heart fails, the primary problem is impairment of ventricular myocardial contractility which results in inadequate cardiac output to meet the metabolic and circulatory demands of the body. Effective therapy of heart failure is accomplished by either enhancing the contractile state of the heart with positive inotropic agents, or by adjusting the peripheral circulatory state with peripheral vasodilators. Agents which stimulate myocardial contractility are of considerable value in the treatment of heart failure. Conventional therapy for heart failure has been the use of digitalis preparations which are the only orally effective inotropic drugs available for use in the treatment of this condition. However, their peripheral vascular effects are undesirable. Sympathomimetic amines are the other major class of cardiac stimulants which are used for the treatment of heart failure. The use of these agents is likewise limited, because they are not fully effective when administered orally and because of undesirable peripheral vasoconstrictor action. Currently, dobutamine and dopamine are the sympathomimetic agents which are primarily used for heart failure, but they can only be administered parenterally.
Several promising inotropic agents which have been studied clinically are the pyridones, amrinone and milrinone, having the following formula: ##STR3## Amrinone is effective in treating patients with heart failure but its use has been severely restricted to acute use only because it has been associated with a high incidence of serious side effects.
Milrinone is undergoing clinical testing as an inotropic agent and its usefulness has not yet been established.
Because of the limitations of currently available drugs in the treatment of heart failure, there is a clear need for new, effective and safe drugs of this type.